Drug addiction is defined as an urge to consume the same drug repeatedly and development of drug dependence. Usually drug addiction is accompanied by development of tolerance to the addictive substance leading to heighten craving, and it becomes necessary to increase the dose of the substance in order to reach the desired effect of the drug. When the user stops taking the drug, he develops withdrawal symptoms that can include mental disorders and severe physical pain. Drug abuse is a global problem and each year drug use-related deaths occur, mainly due to repeated exposure to the drug and drug addiction effects on brain function. Neuropsychotic drugs causes changes in behavior and physiology which might differ depending on the amount of the drug that reaches a specific region of the brain and the release and function of various neurotransmitters that are affected by the drug. Despite the differences between the addictive substances, they all have in common an impact on the reward system in the brain.
Cocaine addiction poses a serious problem to society. Countless deaths occur worldwide as a result of cocaine abuse, levels of which are on the rise. Cocaine craving, induced by drug-associated environmental cues, intensifies or “incubates” over the first few weeks of abstinence, and persists over extended periods of time. As a result, addicts are prone to relapse even after long durations of abstinence. Grimm et al. first demonstrated an analogous incubation phenomenon in rats, in which onset of craving is delayed and craving does not decay, but rather progressively increases over a prolonged period of forced abstinence. According to this model, this time-dependent increase can be modeled. By exposing the rats to intensive training, the researchers showed that cocaine seeking, induced by re-exposure to drug-associated cues, progressively increases over the first two months after withdrawal from cocaine self-administration. This unique phenomenon was called: “the incubation of cocaine craving” and it was investigated by many researchers.
Endogenous opioids stimulate receptors that cause analgesia and reduce pain. Research has distinguished between the mu (μ) opioid type receptor which is stimulated by morphine, the kappa (κ) type which binds ketocyclazocine and the delta (δ) type, which was discovered later. Endogenous opioids bind with different affinities to different kinds of opioid receptors. Most endogenous opioids are derived from three pre-proteins: PDYN, PENK and POMC (pro-opiomelanocortin).
Enzymatic processing of POMC generates β-lipotrophin, cleaved to produce β-endorphin, an endogenous opioid peptide consisting of 31 amino acids. β-endorphin binds at high affinity to the mu and delta opioid receptors (MOR and DOR), while its affinity to kappa opioid receptor (KOR) is lower. As a neurotransmitter in the central nervous system, it is involved in relief of stress and pain, processes of learning and memory, and mediating the rewarding effects of substances of abuse. However, as β-endorphin does not cross the blood-brain barrier (BBB), it can therefore only be given by direct injection to the brain, significantly restricting its clinical application.
New modalities providing safe and effective treatment of cocaine addiction have not appeared despite much effort. There is a need for delta receptor ligands that would both mimic the cocaine craving-reducing effects of β-endorphin and would also be candidates for use in drug rehabilitation therapy. Further, there is a need for highly specific delta receptor agonist that will act as analgesic drugs.